1. Field of the Invention
The present invention relates to a method for treating cardiovascular disorders by administering L-carnitine, an acyl L-carnitine, or a pharmacologically acceptable salt thereof in combination with an ACE-inhibitor. The present invention also relates to orally, parenterally, rectally, or transdermally administrable pharmaceutical compositions suitable for treating cardiovascular disorders, which comprise, as active ingredients, L-carnitine, an acyl L-carnitine, or a pharmacologically acceptable salt thereof and an ACE-inhibitor.
2. Discussion of the Background
Previous therapeutical uses of L-carnitine are already known. For instance, L-carnitine has been used in the cardiovascular field in the treatment of acute and chronic myocardial ischemia, angina pectoris, cardiac arrhythmias and cardiac insufficiency. In nephrology, L-carnitine has been administered to chronic uremic patients who are subjected to regular hemodialysis treatment with a view to counteracting muscular asthenia and the onset of muscular cramps. Further therapeutic uses are the restoration of the HDL/LDL+VLDL ratio to normal and in total parenteral nutrition. The use of L-carnitine for the treatment of certain myopathies and muscular dystrophies is also known.
The ACE-inhibitors form a class of medicaments that has been recently introduced and are capable of preventing the conversion of angiotensin I into angiotensin II, with a consequent anti-hypertensive effect.
Typical ACE-inhibitors include: captopril, enalapril, lisinopril, ramipril, fosinopril, zofenopril, pivopril, rentiapril, quinapril, indolapril, spirapril, pentopril, benazepril, libenzapril, cilazapril, delapril and perindopril.
The main indications for which ACE-inhibitors are used are essential hypertension and renovascular hypertension.
Recently, combination preparations of ACE-inhibitors with various types of other medicaments have been proposed for the treatment of diverse pathological conditions. Examples of such combination preparations and the relative therapeutic indications are set out in Table 1.
TABLE 1 ______________________________________ Known combination preparations of ACE-inhibitors with other medicaments Medicaments Indications Reference ______________________________________ Captopril + diltiazem hypertension US 4,871,731 ACE-inhibitors + calcium loss of cognitive EP 0 344 995 antagonists functions, Alzheimer, senile dementia ACE-inhibitors + myocardiac post- EP 0 366 033 thrombolitics ischaemia disfunction ACE-inhibitor + lithium depression US 4,912,096 ACE-inhibitors + calcium medicament addiction EP 381 075 antagonists ACE-inhibitors + calcium appetite suppression EP 381 074 antagonists ACE-inhibitor + flosequinam cardiopathies WO 90/10445 myocardiac infarction ______________________________________
The combinations set out above, particularly if used in the cardiovascular field, do not appear to be wholly satisfactory in that it is foreseeable that the improved therapeutic activity would be accompanied by at least the sum of the side effects of the ACE-inhibitors themselves on the one hand and on the other hand the side effects of the medicaments combined with them.
In particular, in the case of the compositions containing calcium antagonists, side effects caused by excessive peripheral vasodilatation with consequent tachycardial reflex effects are to be expected.
With regard to the use of acyl carnitines in combination with other medicaments, U.S. Pat. No. 4,537,772 discloses combinations of acyl carnitines (in which the acyl group can be saturated C.sub.2 -C.sub.20 acyl, C.sub.2 -C.sub.20 acyl with 1-6 double bonds, C.sub.2 -C.sub.20 hydroxyacyl with 1-3 hydroxyl groups, C.sub.4 -C.sub.20 ketoacyl, unsaturated C.sub.5 -C.sub.20 hydroxyacyl or C.sub.5 -C.sub.20 carbalkoxyacyl) and their pharmacologically acceptable salts in combination with various classes of medicaments, such as beta-lactamase antibiotics, aminoglycosidic antibiotics, antiviral agents, amino acids, relaxing agents for the smooth musculature, polypeptides, anti-inflammatory agents and diuretics. The only example supplied in U.S. Pat. No. 4,537,772 of combination between an acyl carnitine and a medicament with cardiovascular anti-hypertensive action is a combination of palmitoyl carnitine chloride and methyl dopa. The effect foreseen in U.S. Pat. No. 4,537,772 consists of improved gastrointestinal absorption (induced by the presence of the acyl carnitine) of a medicament which is poorly absorbed when administered on its own by the oral or rectal route. It is clear that there is no correlation between the use of acyl carnitines described in U.S. Pat. No. 4,537,772 and that which forms the subject of the present invention.
Thus, there remains a need for a method to treat cardiovascular disorders. There also remains a need for pharmaceutical compositions useful for treating cardiovascular disorders.